Inhibitors of human immunodeficiency virus replication

ABSTRACT

The disclosure generally relates to compounds of formula I, including compositions and methods for treating human immunodeficiency virus (HIV) infection. The disclosure provides novel inhibitors of HIV, pharmaceutical compositions containing such compounds, and methods for using these compounds in the treatment of HIV infection.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application Ser.No. 61/607,184 filed Mar. 6, 2012.

BACKGROUND OF THE INVENTION

The disclosure generally relates to compounds, compositions, and methodsfor the treatment of human immunodeficiency virus (HIV) infection. Thedisclosure provides novel inhibitors of HIV, pharmaceutical compositionscontaining such compounds, and methods for using these compounds in thetreatment of HIV infection.

Human immunodeficiency virus (HIV) has been identified as theetiological agent responsible for acquired immune deficiency syndrome(AIDS), a fatal disease characterized by destruction of the immunesystem and the inability to fight off life threatening opportunisticinfections. Recent statistics indicate that as many as 33 million peopleworldwide are infected with the virus (UNAIDS: Report on the GlobalHIV/AIDS Epidemic, December 1998). In addition to the large number ofindividuals already infected, the virus continues to spread. Estimatesfrom 1998 point to close to 6 million new infections in that year alone.In the same year there were approximately 2.5 million deaths associatedwith HIV and AIDS.

There are currently a number of antiviral drugs available to combat theinfection. These drugs can be divided into classes based on the viralprotein they target or their mode of action. In particular, saquinavir,indinavir, ritonavir, nelfinavir atazanavir darunavir, amprenavir,fosamprenavir, lopinavir and tipranavir are competitive inhibitors ofthe aspartyl protease expressed by HIV. Zidovudine, didanosine,stavudine, lamivudine, zalcitabine, emtricitibine, tenofovir andabacavir are nucleos(t)ide reverse transcriptase inhibitors that behaveas substrate mimics to halt viral cDNA synthesis. The non-nucleosidereverse transcriptase inhibitors nevirapine, delavirdine, efavirenz andetravirine inhibit the synthesis of viral cDNA via a non-competitive (oruncompetitive) mechanism. Enfuvirtide and maraviroc inhibit the entry ofthe virus into the host cell. An HIV integrase inhibitor, raltegravir(MK-0518, Isentress®), has also been approved for use in treatmentexperienced patients, and it is clear that this class of inhibitors isvery effective as part of a combination regimen containing HIVinhibitors of different classes.

Used alone, these drugs are effective in reducing viral replication:however, the effect is only temporary as the virus readily developsresistance to all known agents used as monotherapy. However, combinationtherapy has proven very effective at both reducing virus and suppressingthe emergence of resistance in a number of patients. In the US, wherecombination therapy is widely available, the number of HIV-relateddeaths has dramatically declined (Palella, F. J.; Delany, K. M.;Moorman, A. C.; Loveless, M. O.; Further, J.; Satten, G. A.; Aschman, D.J.; Holmberg, S. D. N. Engl. J. Med. 1998, 338, 853-860).

Unfortunately, not all patients are responsive and a large number failthis therapy. In fact, initial studies suggest that approximately 30-50%of patients ultimately fail at least one drug in the suppressivecombination. Treatment failure in most cases is caused by the emergenceof viral resistance. Viral resistance in turn is caused by thereplication rate of HIV-1 during the course of infection combined withthe relatively high viral mutation rate associated with the viralpolymerase and the lack of adherence of HIV-infected individuals intaking their prescribed medications. Clearly, there is a need for newantiviral agents, preferably with activity against viruses alreadyresistant to currently approved drugs. Other important factors includeimproved safety and a more convenient dosing regimen than many of thecurrently approved drugs.

Compounds which inhibit HIV replication have been disclosed. SeeWO2007131350, WO2009062285, WO2009062288, WO2009062289, WO2009062308,WO2010130034, WO2010130842, WO2011015641, WO2011076765, WO2012003497 andWO2012003498.

The invention provides technical advantages, for example, the compoundsare novel and are useful in the treatment of HIV. Additionally, thecompounds provide advantages for pharmaceutical uses, for example, withregard to one or more of their mechanism of action, binding, inhibitionefficacy, target selectivity, solubility, safety profiles, orbioavailability.

DESCRIPTION OF THE INVENTION

The invention encompasses compounds of Formula I, includingpharmaceutically acceptable salts, their pharmaceutical compositions,and their use in inhibiting HIV integrase and treating those infectedwith HIV or AIDS.

One aspect of the invention is a compound of Formula I

where:R¹ is N(R⁶)(R⁷);R² is hydrogen, halo, or alkyl;R³ is alkyl, cycloalkyl, or Ar¹;R⁴ is alkyl or haloalkyl;R⁵ is alkyl;R⁶ is hydrogen, alkyl, haloalkyl, (cycloalkyl)alkyl, (Ar²)alkyl,cycloalkyl, (alkyl)cycloalkyl, (Ar²)cycloalkyl, (alkyl)CO,(haloalkyl)CO, ((cycloalkyl)alkyl)CO, (Ar²)CO, ((Ar²)alkyl)CO,((Ar²)alkyl)OCO, ((Ar²)alkyl)NHCO, or ((Ar²)alkyl)COCO;or R⁶ is ((trialkylsilyl)alkyl)OCO, (benzyloxy)alkylCO,(phenoxyalkyl)CO, (isoindolinedionyl)alkyl)CO,(((dialkyl)cycloalkoxy)alkyl)CO, (phenoxyalkyl)CO, or(dihalobenzodioxolyl)CO;R⁷ is hydrogen or alkyl;or N(R⁶)(R⁷) taken together is azetidinyl, pyrrolidinyl, piperidinyl,piperazinyl, morpholinyl, homopiperidinyl, homopiperazinyl, orhomomorpholinyl, and is substituted with 0-3 substituents selected fromhalo, alkyl, haloalkyl, hydroxy, alkoxy, or haloalkoxy; andAr¹ is phenyl, pyridinyl, indanyl, naphthyl, tetrahydronaphthalenyl,benzofuranyl, dihydrobenzofuranyl, benzodioxyl, chromanyl, isochromanyl,benzodioxanyl, quinolinyl, tetrahydroquinolinyl, isoquinolinyl,tetrahydroisoquinolinyl, dihydrobenzoxazinyl, indolyl, dihydroindolyl,benzthiazolyl, or benzothiazolyl, and is substituted with 0-3substituents selected from halo, cyano, alkyl, haloalkyl, cycloalkyl,halocycloalkyl, hydroxy, alkoxy, haloalkoxy, phenoxy, benzyloxy,thioalkyl, and acetamido;or Ar¹ is

Ar² is phenyl, biphenyl, pyrazolyl, indolyl, or fluorenonyl, and issubstituted with 0-3 substituents selected from cyano, halo, alkyl,haloalkyl, cycloalkyl, halocycloalkyl, alkoxy, benzyloxy, andhaloalkoxy;or a pharmaceutically acceptable salt thereof.Another aspect of the invention is a compound of formula I where:R¹ is N(R⁶)(R⁷);R² is hydrogen;R³ is Ar¹;R⁴ is alkyl;R⁵ is alkyl;R⁶ is hydrogen, alkyl, haloalkyl, (cycloalkyl)alkyl, (Ar²)alkyl,cycloalkyl, (alkyl)CO, ((cycloalkyl)alkyl)CO, (Ar²)CO, ((Ar²)alkyl)CO,((Ar²)alkyl)OCO, ((Ar²)alkyl)NHCO, or ((Ar²)alkyl)COCO;or R⁶ is ((trialkylsilyl)alkyl)OCO, (benzyloxy)alkylCO,(phenoxyalkyl)CO, (isoindolinedionyl)alkyl)CO,(((dialkyl)cycloalkoxy)alkyl)CO, (phenoxyalkyl)CO, or(dihalobenzodioxolyl)CO;R⁷ is hydrogen or alkyl;or where N(R⁶)(R⁷) taken together is pyrrolidinyl or piperidinyl, and issubstituted with 0-3 substituents selected from halo, alkyl, haloalkyl,hydroxy, alkoxy, and haloalkoxy;Ar¹ is chromanyl substituted with 0-3 substituents selected from halo,cyano, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, hydroxy, alkoxy,haloalkoxy, phenoxy, benzyloxy, thioalkyl, and acetamido; andAr² is phenyl, pyrazolyl, indolyl, or fluorenonyl, and is substitutedwith 0-3 substituents selected from cyano, halo, alkyl, haloalkyl,cycloalkyl, halocycloalkyl, alkoxy, benzyloxy, and haloalkoxy;or a pharmaceutically acceptable salt thereof.Another aspect of the invention is a compound of formula I where R² ishydrogen.Another aspect of the invention is a compound of formula I where R³ isAr¹.Another aspect of the invention is a compound of formula I where R⁴ isalkyl.Another aspect of the invention is a compound of formula I where R⁶ ishydrogen, alkyl, haloalkyl, (cycloalkyl)alkyl, (Ar²)alkyl, cycloalkyl,(alkyl)CO, ((cycloalkyl)alkyl)CO, (Ar²)CO, ((Ar²)alkyl)CO,((Ar²)alkyl)OCO, ((Ar²)alkyl)NHCO, or ((Ar²)alkyl)COCO.Another aspect of the invention is a compound of formula I whereN(R⁶)(R⁷) taken together is azetidinyl, pyrrolidinyl, piperidinyl,piperazinyl, morpholinyl, homopiperidinyl, homopiperazinyl, orhomomorpholinyl, and is substituted with 0-3 substituents selected fromhalo, alkyl, haloalkyl, hydroxy, alkoxy, or haloalkoxy.Another aspect of the invention is a compound of formula I whereN(R⁶)(R⁷) taken together is pyrrolidinyl or piperidinyl, and issubstituted with 0-3 substituents selected from halo, alkyl, haloalkyl,hydroxy, alkoxy, and haloalkoxy.Another aspect of the invention is a compound of formula I where Ar¹ ischromanyl substituted with 0-3 substituents selected from halo, cyano,alkyl, haloalkyl, cycloalkyl, halocycloalkyl, hydroxy, alkoxy,haloalkoxy, phenoxy, benzyloxy, thioalkyl, and acetamido.Another aspect of the invention is a compound of formula I where Ar² isphenyl, pyrazolyl, indolyl, or fluorenonyl, and is substituted with 0-3substituents selected from cyano, halo, alkyl, haloalkyl, cycloalkyl,halocycloalkyl, alkoxy, benzyloxy, and haloalkoxy.Another aspect of the invention is a compound of formula I where Ar² isphenyl substituted with 0-3 substituents selected from cyano, halo,alkyl, haloalkyl, cycloalkyl, halocycloalkyl, alkoxy, benzyloxy, andhaloalkoxy.

For a compound of Formula I, the scope of any instance of a variablesubstituent, including R¹, R², R³, R⁴, R⁵, R⁶, R⁷, Ar¹, and Ar², can beused independently with the scope of any other instance of a variablesubstituent. As such, the invention includes combinations of thedifferent aspects.

Unless specified otherwise, these terms have the following meanings.“Halo” includes fluoro, chloro, bromo, and iodo. “Alkyl” means astraight or branched alkyl group composed of 1 to 10 carbons, morepreferably 1 to 6 carbons. “Alkenyl” means a straight or branched alkylgroup composed of 2 to 10 carbons, more preferably 2 to 6 carbons, withat least one double bond. “Alkynyl” means a straight or branched alkylgroup composed of 2 to 10 carbons, more preferably 2 to 6 carbons, withat least one triple bond. “Cycloalkyl” means a monocyclic ring systemcomposed of 3 to 7 carbons. “Haloalkyl” and “haloalkoxy” include allhalogenated isomers from monohalo to perhalo. Terms with a hydrocarbonmoiety (e.g. alkoxy) include straight and branched isomers for thehydrocarbon portion. “Aryl” means a monocyclic or bicyclic aromatichydrocarbon groups having 6 to 12 carbon atoms, or a bicyclic fused ringsystem wherein one or both of the rings is a phenyl group. Bicyclicfused ring systems consist of a phenyl group fused to a four- tosix-membered aromatic or non-aromatic carbocyclic ring. Representativeexamples of aryl groups include, but are not limited to, indanyl,indenyl, naphthyl, phenyl, and tetrahydronaphthyl. “Heteroaryl” means a5 to 7 membered monocyclic or 8 to 11 membered bicyclic aromatic ringsystem with 1-5 heteroatoms independently selected from nitrogen,oxygen, and sulfur. Parenthetic and multiparenthetic terms are intendedto clarify bonding relationships to those skilled in the art. Forexample, a term such as ((R)alkyl) means an alkyl substituent furthersubstituted with the substituent R.

The invention includes all pharmaceutically acceptable salt forms of thecompounds. Pharmaceutically acceptable salts are those in which thecounter ions do not contribute significantly to the physiologicalactivity or toxicity of the compounds and as such function aspharmacological equivalents. These salts can be made according to commonorganic techniques employing commercially available reagents. Someanionic salt forms include acetate, acistrate, besylate, bromide,chloride, citrate, fumarate, glucouronate, hydrobromide, hydrochloride,hydroiodide, iodide, lactate, maleate, mesylate, nitrate, pamoate,phosphate, succinate, sulfate, tartrate, tosylate, and xinofoate. Somecationic salt forms include ammonium, aluminum, benzathine, bismuth,calcium, choline, diethylamine, diethanolamine, lithium, magnesium,meglumine, 4-phenylcyclohexylamine, piperazine, potassium, sodium,tromethamine, and zinc.

Some of the compounds of the invention exist in stereoisomeric forms.The invention includes all stereoisomeric forms of the compoundsincluding enantiomers and diastereromers. Methods of making andseparating stereoisomers are known in the art. The invention includesall tautomeric forms of the compounds. The invention includesatropisomers and rotational isomers.

The invention is intended to include all isotopes of atoms occurring inthe present compounds. Isotopes include those atoms having the sameatomic number but different mass numbers. By way of general example andwithout limitation, isotopes of hydrogen include deuterium and tritium.Isotopes of carbon include ¹³C and ¹⁴C. Isotopically-labeled compoundsof the invention can generally be prepared by conventional techniquesknown to those skilled in the art or by processes analogous to thosedescribed herein, using an appropriate isotopically-labeled reagent inplace of the non-labeled reagent otherwise employed. Such compounds mayhave a variety of potential uses, for example as standards and reagentsin determining biological activity. In the case of stable isotopes, suchcompounds may have the potential to favorably modify biological,pharmacological, or pharmacokinetic properties.

Biological Methods

Inhibition of HIV Replication.

A recombinant NL-Rluc virus was constructed in which a section of thenef gene from NL4-3 was replaced with the Renilla Luciferase gene. TheNL-RLuc virus was prepared by co-transfection of two plasmids, pNLRLucand pVSVenv. The pNLRLuc contains the NL-Rluc DNA cloned into pUC18 atthe PvuII site, while the pVSVenv contains the gene for VSV G proteinlinked to an LTR promoter. Transfections were performed at a 1:3 ratioof pNLRLuc to pVSVenv in 293T cells using the LipofectAMINE PLUS kitfrom Invitrogen (Carlsbad, Calif.) according to the manufacturer, andthe pseudotype virus generated was titered in MT-2 cells. Forsusceptibility analyses, the titrated virus was used to infect MT-2cells in the presence of compound, and after 5 days of incubation, cellswere processed and quantitated for virus growth by the amount ofexpressed luciferase. This provides a simple and easy method forquantitating the extent of virus growth and consequently, the antiviralactivity of test compounds. Luciferase was quantitated using the DualLuciferase kit from Promega (Madison, Wis.).

Susceptibility of viruses to compounds was determined by incubation inthe presence of serial dilutions of the compound. The 50% effectiveconcentration (EC₅₀) was calculated by using the exponential form of themedian effect equation where (Fa)=1/[1+(ED₅₀/drug conc.)^(m)] (Johnson VA, Byington R T. Infectivity Assay. In Techniques in HIV Research. ed.Aldovini A, Walker B D. 71-76. New York: Stockton Press. 1990). Theanti-viral activity of compounds was evaluated under three serumconditions, 10% FBS, 15 mg/ml human serum albumin/10% FBS or 40% humanserum/5% FBS, and the results from at least 2 experiments were used tocalculate the EC₅₀ values. Results are shown in Table 1. Activity equalto A refers to a compound having an EC₅₀≦100 nM, while B and C denotecompounds having an EC₅₀ between 100 nM and 1 uM (B) or >1 uM (C).

TABLE 1 Example Activity EC₅₀ (μM) 1 C 2.48 2 A 3 A 0.08 4 B 0.12 5 A 6A 7 A 8 B 9 A 10 A 11 A 12 A 0.05 13 A 14 A 15 B 0.26 16 B 17 A 18 B 19A 20 A 21 A 22 B 23 B 0.17 24 A 25 A 26 A 27 B 28 A 29 B 30 nd 31 A 32 C6.41 33 A 0.06 34 A 35 A 36 A 37 A 38 B 0.30 39 A 40 A 41 A 0.05 42 A 43A 44 C 1.60 45 A 46 C 2.57 47 A 48 B 0.34 49 B 50 A 0.06 51 B 52 A

Pharmaceutical Composition and Methods of Use

The compounds of this invention inhibit HIV replication. Accordingly,another aspect of the invention is a method for treating HIV infectionin a human patient comprising administering a therapeutically effectiveamount of a compound of Formula I, or a pharmaceutically acceptable saltthereof, with a pharmaceutically acceptable carrier.

Another aspect of the invention is the use of a compound of formula I inthe manufacture of a medicament for the treatment of AIDS or HIVinfection.

Another aspect of the invention is a method for treating HIV infectionin a human patient comprising the administration of a therapeuticallyeffective amount of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, with a therapeutically effective amount of atleast one other agent used for treatment of AIDS or HIV infectionselected from the group consisting of nucleoside HIV reversetranscriptase inhibitors, non-nucleoside HIV reverse transcriptaseinhibitors, HIV protease inhibitors, HIV fusion inhibitors, HIVattachment inhibitors, CCR5 inhibitors, CXCR4 inhibitors, HIV budding ormaturation inhibitors, and HIV integrase inhibitors.

Another aspect of the invention is a method wherein the agent is anucleoside HIV reverse transcriptase inhibitor.

Another aspect of the invention is a method wherein the nucleoside HIVreverse transcriptase inhibitor is selected from the group consisting ofabacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir,zalcitabine, and zidovudine, or a pharmaceutically acceptable saltthereof.

Another aspect of the invention is a method wherein the agent is anon-nucleoside HIV reverse transcriptase inhibitor.

Another aspect of the invention is a method wherein the non-nucleosideHIV reverse transcriptase inhibitor is selected from the groupconsisting of delavirdine, efavirenz, and nevirapine, or apharmaceutically acceptable thereof.

Another aspect of the invention is a method wherein the agent is an HIVprotease inhibitor.

Another aspect of the invention is a method wherein the HIV proteaseinhibitor is selected from the group consisting of amprenavir,atazanavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir andfosamprenavir, or a pharmaceutically acceptable salt thereof.

Another aspect of the invention is a method wherein the agent is an HIVfusion inhibitor.

Another aspect of the invention is a method wherein the HIV fusioninhibitor is enfuvirtide or T-1249, or a pharmaceutically acceptablesalt thereof.

Another aspect of the invention is a method wherein the agent is an HIVattachment inhibitor.

Another aspect of the invention is a method wherein the agent is a CCR5inhibitor.

Another aspect of the invention is a method wherein the CCR5 inhibitoris selected from the group consisting of Sch-C, Sch-D, TAK-220, PRO-140,and UK-427,857, or a pharmaceutically acceptable salt thereof.

Another aspect of the invention is a method wherein the agent is a CXCR4inhibitor.

Another aspect of the invention is a method wherein the CXCR4 inhibitoris AMD-3100, or a pharmaceutically acceptable salt thereof.

Another aspect of the invention is a method wherein the agent is an HIVbudding or maturation inhibitor.

Another aspect of the invention is a method wherein the budding ormaturation inhibitor is PA-457, or a pharmaceutically acceptable saltthereof.

Another aspect of the invention is a method wherein the agent is an HIVintegrase inhibitor.

Another aspect of the invention is a pharmaceutical compositioncomprising a therapeutically effective amount of a compound of FormulaI, or a pharmaceutically acceptable salt thereof, with at least oneother agent used for treatment of AIDS or HIV infection selected fromthe group consisting of nucleoside HIV reverse transcriptase inhibitors,non-nucleoside HIV reverse transcriptase inhibitors, HIV proteaseinhibitors, HIV fusion inhibitors, HIV attachment inhibitors, CCR5inhibitors, CXCR4 inhibitors, HIV budding or maturation inhibitors, andHIV integrase inhibitors, and a pharmaceutically acceptable carrier.

Another aspect of the invention is the composition wherein the agent isa nucleoside HIV reverse transcriptase inhibitor.

Another aspect of the invention is the composition wherein thenucleoside HIV transcriptase inhibitor is selected from the groupconsisting of abacavir, didanosine, emtricitabine, lamivudine,stavudine, tenofovir, zalcitabine, and zidovudine, or a pharmaceuticallyacceptable salt thereof.

Another aspect of the invention is the composition wherein the agent isa non-nucleoside HIV reverse transcriptase inhibitor.

Another aspect of the invention is the composition wherein thenon-nucleoside HIV reverse transcriptase inhibitor is selected from thegroup consisting of delavirdine, efavirenz, and nevirapine, or apharmaceutically acceptable salt thereof.

Another aspect of the invention is the composition wherein the agent isan HIV protease inhibitor.

Another aspect of the invention is the composition wherein the HIVprotease inhibitor is selected from the group consisting of amprenavir,atazanavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir andfosamprenavir, or a pharmaceutically acceptable salt thereof.

Another aspect of the invention is the composition wherein the agent isan HIV fusion inhibitor.

Another aspect of the invention is the composition method wherein theHIV fusion inhibitor is enfuvirtide or T-1249, or a pharmaceuticallyacceptable salt thereof.

Another aspect of the invention is the composition wherein the agent isan HIV attachment inhibitor.

Another aspect of the invention is the composition wherein the agent isa CCR5 inhibitor.

Another aspect of the invention is the composition wherein the CCR5inhibitor is selected from the group consisting of Sch-C, Sch-D,TAK-220, PRO-140, and UK-427,857, or a pharmaceutically acceptable saltthereof.

Another aspect of the invention is a method wherein the agent is a CXCR4inhibitor.

Another aspect of the invention is a method wherein the CXCR4 inhibitoris AMD-3100 or a pharmaceutically acceptable salt thereof.

Another aspect of the invention is the composition wherein the agent isan HIV budding or maturation inhibitor.

Another aspect of the invention is the composition wherein the buddingor maturation inhibitor is PA-457, or a pharmaceutically acceptable saltthereof.

Another aspect of the invention is the composition wherein the agent isan HIV integrase inhibitor.

“Combination,” “coadministration,” “concurrent” and similar termsreferring to the administration of a compound of Formula I with at leastone anti-HIV agent mean that the components are part of a combinationantiretroviral therapy or highly active antiretroviral therapy (HAART)as understood by practitioners in the field of AIDS and HIV infection.

“Therapeutically effective” means the amount of agent required toprovide a meaningful patient benefit as understood by practitioners inthe field of AIDS and HIV infection. In general, the goals of treatmentare suppression of viral load, restoration and preservation ofimmunologic function, improved quality of life, and reduction ofHIV-related morbidity and mortality.

“Patient” means a person infected with the HIV virus and suitable fortherapy as understood by practitioners in the field of AIDS and HIVinfection.

“Treatment,” “therapy,” “regimen,” “HIV infection,” “ARC,” “AIDS” andrelated terms are used as understood by practitioners in the field ofAIDS and HIV infection.

The compounds of this invention are generally given as pharmaceuticalcompositions comprised of a therapeutically effective amount of acompound of Formula I or its pharmaceutically acceptable salt and apharmaceutically acceptable carrier and may contain conventionalexcipients. A therapeutically effective amount is that which is neededto provide a meaningful patient benefit. Pharmaceutically acceptablecarriers are those conventionally known carriers having acceptablesafety profiles. Compositions encompass all common solid and liquidforms including capsules, tablets, losenges, and powders as well asliquid suspensions, syrups, elixers, and solutions. Compositions aremade using common formulation techniques, and conventional excipients(such as binding and wetting agents) and vehicles (such as water andalcohols) are generally used for compositions. See, for example,Remington's Pharmaceutical Sciences, 17th edition, Mack PublishingCompany, Easton, Pa. (1985).

Solid compositions are normally formulated in dosage units andcompositions providing from about 1 to 1000 mg of the active ingredientper dose are preferred. Some examples of dosages are 1 mg, 10 mg, 100mg, 250 mg, 500 mg, and 1000 mg. Generally, other antiretroviral agentswill be present in a unit range similar to agents of that class usedclinically. Typically, this is 0.25-1000 mg/unit.

Liquid compositions are usually in dosage unit ranges. Generally, theliquid composition will be in a unit dosage range of 1-100 mg/mL. Someexamples of dosages are 1 mg/mL, 10 mg/mL, 25 mg/mL, 50 mg/mL, and 100mg/mL. Generally, other antiretroviral agents will be present in a unitrange similar to agents of that class used clinically. Typically, thisis 1-100 mg/mL.

The invention encompasses all conventional modes of administration; oraland parenteral methods are preferred. Generally, the dosing regimen willbe similar to other antiretroviral agents used clinically. Typically,the daily dose will be 1-100 mg/kg body weight daily. Generally, morecompound is required orally and less parenterally. The specific dosingregime, however, will be determined by a physician using sound medicaljudgement.

The invention also encompasses methods where the compound is given incombination therapy. That is, the compound can be used in conjunctionwith, but separately from, other agents useful in treating AIDS and HIVinfection. Some of these agents include HIV attachment inhibitors, CCR5inhibitors, CXCR4 inhibitors, HIV cell fusion inhibitors, HIV integraseinhibitors, HIV nucleoside reverse transcriptase inhibitors, HIVnon-nucleoside reverse transcriptase inhibitors, HIV proteaseinhibitors, budding and maturation inhibitors, immunomodulators, andanti-infectives. In these combination methods, the compound of Formula Iwill generally be given in a daily dose of 1-100 mg/kg body weight dailyin conjunction with other agents. The other agents generally will begiven in the amounts used therapeutically. The specific dosing regime,however, will be determined by a physician using sound medicaljudgement.

Synthetic Methods

The compounds of this invention can be made by various methods known inthe art including those of the following schemes and in the specificembodiments section. The structure numbering and variable numberingshown in the synthetic schemes are distinct from, and should not beconfused with, the structure or variable numbering in the claims or therest of the specification. The variables in the schemes are meant onlyto illustrate how to make some of the compounds of this invention.

The disclosure is not limited to the foregoing illustrative examples andthe examples should be considered in all respects as illustrative andnot restrictive, reference being made to the appended claims, ratherthan to the foregoing examples, and all changes which come within themeaning and range of equivalency of the claims are therefore intended tobe embraced.

Abbreviations used in the schemes and examples generally followconventions used in the art. Chemical abbreviations used in thespecification and examples are defined as follows: “KHMDS” for potassiumbis(trimethylsilyl)amide; “DMF” for N,N-dimethylformamide; “HATU” forO-(t-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate, “MeOH” for methanol; “Ar” for aryl; “TFA” fortrifluoroacetic acid, “DMSO” for dimethylsulfoxide; “h” for hours; “rt”for room temperature or retention time (context will dictate); “min” forminutes; “EtOAc” for ethyl acetate; “THF” for tetrahydrofuran; “Et₂O”for diethyl ether; “DMAP” for 4-dimethylaminopyridine; “DCE” for1,2-dichloroethane; “ACN” for acetonitrile; “DME” for1,2-dimethoxyethane; “HOBt” for 1-hydroxybenzotriazole hydrate; and“DIEA” for diisopropylethylamine

Abbreviations as used herein, are defined as follows: “1×” for once,“2×” for twice, “3×” for thrice, “° C.” for degrees Celsius, “eq” forequivalent or equivalents, “g” for gram or grams, “mg” for milligram ormilligrams, “L” for liter or liters, “mL” for milliliter or milliliters,“μL” for microliter or microliters, “N” for normal, “M” for molar,“mmol” for millimole or millimoles, “atm” for atmosphere, “psi” forpounds per square inch, “conc.” for concentrate, “sat” or “sat'd” forsaturated, “MW” for molecular weight, “mp” for melting point, “ee” forenantiomeric excess, “MS” or “Mass Spec” for mass spectrometry, “ESI”for electrospray ionization mass spectroscopy, “HR” for high resolution,“HRMS” for high resolution mass spectrometry, “LCMS” for liquidchromatography mass spectrometry, “HPLC” for high pressure liquidchromatography, “RP HPLC” for reverse phase HPLC, “TLC” or “tlc” forthin layer chromatography, “NMR” for nuclear magnetic resonancespectroscopy, “¹H” for proton, “δ” for delta, “s” for singlet, “d” fordoublet, “t” for triplet, “q” for quartet, “m” for multiplet, “br” forbroad, “Hz” for hertz, and “α”, “β”, “R”, “S”, “E”, and “Z” arestereochemical designations familiar to one skilled in the art.

Some compounds can be synthesized from an appropriately substitutedheterocycle I-1 according to Scheme I, Compound I-1 and I-2 arecommercially available or synthesized by reactions well known in theart. Intermediates I-3 can be prepared by procedure well known in theart or as set forth in the examples below using compound I-1 andcompound I-2. Intermediates I-3 are conveniently transformed tointermediates I-5 via intermediates I-4 using conditions well-known tothose skilled in the art. Intermediates I-5 are oxidized tointermediates I-6 by reactions well-known in the art, including but notlimited to Davis oxidation. Intermediates I-6 are oxidized tointermediates I-7 by a well-known conditions, including but not limitedto Dess-Martin oxidation. Intermediates I-7 are reduced to chiralintermediates I-8 using well-known conditions in the presence ofcatalytic chiral ligands. Intermediates I-8 are converted to theintermediates I-9 by well-known conditions, including but not limited totertiary-butyl acetate and perchloric acid. Intermediates I-9 areconveniently transformed to intermediates I-10 using conditionswell-known in the art, including but not limited to the Suzuki couplingbetween intermediates I-9 and R₄—B(OR)₂. The boronate or boronic acidcoupling reagents are commercially available or are prepared byreactions well-known to those skilled in the art (PCT Appln.WO20090662285). The intermediates I-10 are regioselectively converted tointermediates I-11 by methods well-known in the art. Intermediates I-11are conveniently converted to intermediates I-12 by conditionswell-known to those skilled in the art, including but not limited toDPPA and appropriate base. Intermediates I-12 are transformed tointermediates I-13 using conditions well-known to those skilled in theart. Hydrolysis of intermediates I-13 using the conditions well known tothose skilled in the art provided the carboxylic acids I-14. Theintermediates I-14 were transformed to final compounds I-15 byconditions well known in the literature. In addition, the intermediatesI-14 could also be transformed to final compound I-16 by reductivealkylation using conditions well to those skilled in art.

The compounds described herein were purified by the methods well knownto those skilled in art by normal phase column chromatography on silicagel column using appropriate solvent system described. All preparativeHPLC purifications mentioned in this experimentation section werecarried out gradient elution either on Sunfire Prep C18 ODB column (5μm; 19×100 mm) or Waters Xbridge column (5 μM; 19×100 mm) using thefollowing mobile phases. For SunFire column mobile phase A: 9:1H₂O/acetonitrile with 10 mM NH₄OAc and mobile phase B: A:9:1acetonitrile/H₂O with: 10 mM NH₄OAc. For Waters Xbride column mobilephase A: water with 20 mM NH₄OAc and mobile phase B: 95:5 MeOH/H₂O with20 mM NH₄OAc.

Ethyl6-(2-ethoxy-2-oxoethyl)-7-hydroxy-5-methylpyrazolo[1,5-a]pyrimidine-2-carboxylate

A suspension of ethyl 5-amino-1H-pyrazole-3-carboxylate (35.5 g, 229mmol, prepared according to WO 2008015271), diethyl 2-acetylsuccinate(51.2 mL, 275 mmol) and TsOH.H₂O (0.218 g, 1.144 mmol) in o-xylene (500mL) was refluxed using a Dean-Stork condensor for 5 h. (Note: Thesuspension turned into a clear homogeneous solution and then in about 15min a yellow solid started precipitated out of solution). Then, thereaction mixture was cooled, diluted with hexanes (250 mL), filtered,washed with hexanes and dried to afford ethyl6-(2-ethoxy-2-oxoethyl)-7-hydroxy-5-methylpyrazolo[1,5-a]pyrimidine-2-carboxylate(53 g, 75% yield) as light yellow solid. 1H NMR (500 MHz, DMSO-d₆) δ12.61 (br. s., 1H), 6.49 (s, 1H), 4.34 (q, J=7.1 Hz, 2H), 4.09 (q, J=7.1Hz, 2H), 3.57 (s, 2H), 2.34 (s, 3H), 1.33 (t, J=7.2 Hz, 3H), 1.19 (t,J=7.0 Hz, 3H). LCMS (M+H)=308.04.

Ethyl7-chloro-6-(2-ethoxy-2-oxoethyl)-5-methylpyrazolo[1,5-a]pyrimidine-2-carboxylate

A mixture of ethyl6-(2-ethoxy-2-oxoethyl)-7-hydroxy-5-methylpyrazolo[1,5-a]pyrimidine-2-carboxylate(25 g, 81 mmol), and N,N-dimethylaniline (20.6 mL, 163 mmol) in POCl₃(100 mL) was heated at 120° C. for 3 h. Then the reaction was cooled tort and concentrated in vacuo to half the volume. It was poured into alarge quantity of ice water and stirred for 20 min. Precipitates formedand were collected by filtration. This solid was dissolved in ethylacetate (1 L) and washed with water. The aqueous phase wasback-extracted with ethyl acetate and the combined organic layers werewashed with brine (200 mL), dried (Na₂SO₄), filtered and concentrated invacuo. The crude was then triturated with EtOAc/hexane to afford ethyl7-chloro-6-(2-ethoxy-2-oxoethyl)-5-methylpyrazolo[1,5-a]pyrimidine-2-carboxylate(22 g, 67.5 mmol, 83% yield) as light yellow solid. 1H NMR (500 MHz,CDCl₃) δ 7.21 (s, 1H), 4.52 (q, J=7.2 Hz, 2H), 4.24 (q, J=7.2 Hz, 2H),3.94 (s, 2H), 2.66 (s, 3H), 1.48 (t, J=7.0 Hz, 3H), 1.30 (t, J=7.2 Hz,3H). LCMS (M+H)=326.2.

Ethyl6-(2-ethoxy-2-oxoethyl)-7-iodo-5-methylpyrazolo[1,5-a]pyrimidine-2-carboxylate

Ethyl7-chloro-6-(2-ethoxy-2-oxoethyl)-5-methylpyrazolo[1,5-a]pyrimidine-2-carboxylate(5 g, 15.35 mmol) and sodium iodide (9.20 g, 61.4 mmol) were suspendedin acetonitrile (80 mL) and the resulting mixture was heated at 80° C.for 2 h. At this point LCMS indicated completion of the reaction andappearance of the desired product. After cooling to rt, the reactionmixture was diluted with ethyl acetate and washed with water and aqueousNa₂S₂O₃. The organic phase was dried (Na₂SO₄), filtered and concentratedin vacuo. The crude product was triturated with ethyl acetate/hexane toafford ethyl6-(2-ethoxy-2-oxoethyl)-7-iodo-5-methylpyrazolo[1,5-a]pyrimidine-2-carboxylate(5.7 g, 13.7 mmol, 89% yield) as an off-white solid. ¹H NMR (500 MHz,CDCl₃) δ 7.32 (s, 1H), 4.51 (d, J=7.0 Hz, 2H), 4.25 (d, J=7.0 Hz, 2H),4.02 (s, 2H), 2.68 (s, 3H), 1.48 (t, J=7.2 Hz, 3H), 1.31 (t, J=7.2 Hz,3H). LCMS (M+H)=418.2.

Ethyl6-(2-ethoxy-1-hydroxy-2-oxoethyl)-7-iodo-5-methylpyrazolo[1,5-a]pyrimidine-2-carboxylate

To a stirred solution of 0.9M KHMDS/THF (39.1 mL, 35.2 mmol) in THF (100mL) at −78° C. was added a THF (50 mL) solution of ethyl6-(2-ethoxy-2-oxoethyl)-7-iodo-5-methylpyrazolo[1,5-a]pyrimidine-2-carboxylate(11.3 g, 27.1 mmol) over the course of 5 min. After 30 min, a THF (50mL) solution of 3-phenyl-2-(phenylsulfonyl)-1,2-oxaziridine (9.20 g,35.2 mmol) was added to the red reaction mixture and stirring wascontinued for an additional 30 min at −78° C. Then, the resulting orangereaction mixture was quenched with sat. aq. NH₄Cl (50 mL), diluted withEtOAc (200 mL), washed with water (100 mL), brine (100 mL), dried(Na₂SO₄), filtered and concentrated in vacuo to give a solid. This solidwas triturated with small amount of ethyl acetate and solids werefiltered, washed with hexanes and dried under high vacuum to affordethyl6-(2-ethoxy-1-hydroxy-2-oxoethyl)-7-iodo-5-methylpyrazolo[1,5-a]pyrimidine-2-carboxylate(7.3 g, 16.85 mmol, 62.2% yield) as light yellow solid. 1H NMR (500 MHz,CDCl₃) δ 7.33 (s, 1H), 5.75 (d, J=2.1 Hz, 1H), 4.52 (qd, J=7.1, 1.2 Hz,2H), 4.37-4.30 (m, 2H), 3.57 (d, J=2.4 Hz, 1H), 2.63 (s, 3H), 1.48 (t,J=7.2 Hz, 3H), 1.27 (t, J=7.0 Hz, 3H). LCMS (M+H)=434.1.

Ethyl6-(2-ethoxy-2-oxoacetyl)-7-iodo-5-methylpyrazolo[1,5-a]pyrimidine-2-carboxylate

To a mixture of ethyl6-(2-ethoxy-1-hydroxy-2-oxoethyl)-7-iodo-5-methylpyrazolo[1,5-a]pyrimidine-2-carboxylate(3.7 g, 6.41 mmol) in CH₂Cl₂ (80 mL) was added Dess-Martin Periodinane(2.72 g, 6.41 mmol) and the resulting mixture was stirred at rt for 1 h.The reaction mixture was diluted with ethyl acetate (500 mL) and washedwith sat. aq. NaHCO₃ solution (100 mL), dried (Na₂SO₄), filtered, andconcentrated in vacuo. The residue was purified by silica gelchromatography (5-70% EtOAc/hexane) to afford the desired ethyl6-(2-ethoxy-2-oxoacetyl)-7-iodo-5-methylpyrazolo[1,5-a]pyrimidine-2-carboxylate(2.5 g, 5.8 mmol, 91% yield) as an off-white solid. 1H NMR (400 MHz,CDCl₃) δ 7.36 (s, 1H), 4.50 (dq, J=14.5, 7.1 Hz, 4H), 2.56 (s, 3H), 1.46(t, J=7.2 Hz, 3H), 1.48 (t, J=7.2 Hz, 3H). LCMS (M+H)=431.87.

(S)-Ethyl6-(2-ethoxy-1-hydroxy-2-oxoethyl)-7-iodo-5-methylpyrazolo[1,5-a]pyrimidine-2-carboxylate

To a stirred yellow solution of ethyl6-(2-ethoxy-2-oxoacetyl)-7-iodo-5-methylpyrazolo[1,5-a]pyrimidine-2-carboxylate(6.4 g, 14.8 mmol) in anhydrous toluene (300 mL) was added 1.1M(R)-1-methyl-3,3-diphenylhexahydropyrrolo[1,2-c][1,3,2]oxazaborole/toluene(5.40 mL, 5.94 mmol). The mixture was cooled to −35° C. and a solutionof 50% catechoborane/toluene (5.09 mL, 20.78 mmol) was added over thecourse of 10 min. After 30 min, the reaction mixture was slowly warmedto −15° C. and stirred for additional 2 h, then diluted with EtOAc (600mL) and sat. aq. Na₂CO₃ (100 mL). The mixture was stirred vigorously for30 min, and the organic phase was washed with sat. aq. Na₂CO₃ (2×100mL), dried (Na₂SO₄), filtered, concentrated. The residue was purified bysilica gel chromatography (5-100% EtOAc/hexane) to afford the desired(S)-ethyl6-(2-ethoxy-1-hydroxy-2-oxoethyl)-7-iodo-5-methylpyrazolo[1,5-a]pyrimidine-2-carboxylate(5.3 g, 12.2 mmol, 82% yield) as an off-white solid. 1H NMR (500 MHz,CDCl₃) δ 7.33 (s, 1H), 5.75 (d, J=2.4 Hz, 1H), 4.52 (qd, J=7.1, 1.1 Hz,2H), 4.38-4.29 (m, 2H), 3.59 (d, J=2.4 Hz, 1H), 2.63 (s, 3H), 1.48 (t,J=7.2 Hz, 3H), 1.27 (t, J=7.2 Hz, 3H). LCMS (M+H)=434.2.

(S)-Ethyl6-(1-(tert-butoxy)-2-ethoxy-2-oxoethyl)-7-iodo-5-methylpyrazolo[1,5-a]pyrimidine-2-carboxylate

To a stirred solution of (S)-ethyl6-(2-ethoxy-1-hydroxy-2-oxoethyl)-7-iodo-5-methylpyrazolo[1,5-a]pyrimidine-2-carboxylate(5.3 g, 12.2 mmol) in CH₂Cl₂ (150 mL) and t-butyl acetate (105 mL) at rtwas added perchloric acid (3.15 mL, 36.7 mmol). The reaction flask wassealed. After stirring for 3 h, the reaction mixture was diluted withCH₂Cl₂ (100 mL), carefully quenched with sat. aq. NaHCO₃ (50 mL). Theorganic layer was separated and washed with brine (100 mL), dried(Na₂SO₄), filtered and concentrated in vacuo to give a yellow liquid.This crude product was purified by flash column chromatography on asilica gel column using (10-50% EtOAc/Hex as eluant) to afford thedesired (S)-ethyl6-(1-(tert-butoxy)-2-ethoxy-2-oxoethyl)-7-iodo-5-methylpyrazolo[1,5-a]pyrimidine-2-carboxylate(4.5 g, 8.28 mmol, 67.7% yield) as viscous oil. In addition, 700 mg ofstarting material was recovered. 1H NMR (500 MHz, CDCl₃) δ 7.31 (s, 1H),5.56 (s, 1H), 4.51 (q, J=7.1 Hz, 2H), 4.26-4.16 (m, 2H), 2.71 (s, 3H),1.48 (t, J=7.2 Hz, 3H), 1.30 (s, 9H), 1.23 (t, J=7.0 Hz, 3H). LCMS(M+H)=490.0.

2-(8-fluoro-5-methylchroman-6-yl)-4,4,5,5-tetramethyl-1,3,2dioxaborolane

The title compound was prepared from the known procedure as described inthe reference WO 2009/062285.

6-((S)-1-(tert-Butoxy)-2-ethoxy-2-oxoethyl)-7-(8-fluoro-5-methylchroman-6-yl)-5-methylpyrazolo[1,5-a]pyrimidine-2-carboxylate

A mixture of (S)-ethyl6-(1-(tert-butoxy)-2-ethoxy-2-oxoethyl)-7-iodo-5-methylpyrazolo[1,5-a]pyrimidine-2-carboxylate(4.5 g, 9.20 mmol),2-(8-fluoro-5-methylchroman-6-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(3.22 g, 11.04 mmol) and 2N Na₂CO₃ (9.20 mL, 18.39 mmol) in DMF (100 mL)was degassed and flushed with N₂ for 30 min.Tetrakis(triphenylphosphine)palladium(0) (0.744 g, 0.644 mmol) was thenadded and the reaction was flushed with N₂ for another 15 min. Themixture was then heated at 100° C. for 16 h. At this point LCMSindicated completion of reaction and appearance of desired product.After cooling to rt, water was added (50 mL) and the mixture wasextracted with ether (2×200 mL). The organic phase was washed with brine(100 mL), dried (Na₂SO₄), filtered and concentrated in vacuo. Theresidue was then purified by silica gel chromatography (5-60%EtOAc/hexane) to afford ethyl6-((S)-1-(tert-butoxy)-2-ethoxy-2-oxoethyl)-7-(8-fluoro-5-methylchroman-6-yl)-5-methylpyrazolo[1,5-a]pyrimidine-2-carboxylate(4 g, 7.58 mmol, 82% yield) as mixture of atrope isomers (approx 10% ofminor atrope isomer was present). 1H NMR (500 MHz, CDCl₃) δ 7.10 (s,1H), 6.87 (d, J=10.7 Hz, 1H), 5.00 (s, 1H), 4.41 (qd, J=7.1, 3.1 Hz,2H), 4.35 (dd, J=5.2, 4.0 Hz, 2H), 4.14 (q, J=7.2 Hz, 2H), 2.80 (s, 3H),2.79-2.73 (m, 2H), 2.23-2.15 (m, 2H), 1.82 (s, 3H), 1.41 (t, J=7.2 Hz,3H), 1.22-1.19 (m, 4H), 1.18 (s, 9H). LCMS (M+H)=528.4.

6-((S)-1-(tert-Butoxy)-2-ethoxy-2-oxoethyl)-7-(8-fluoro-5-methylchroman-6-yl)-5-methylpyrazolo[1,5-a]pyrimidine-2-carboxylicacid

To a solution of ethyl6-((S)-1-(tert-butoxy)-2-ethoxy-2-oxoethyl)-7-(8-fluoro-5-methylchroman-6-yl)-5-methylpyrazolo[1,5-a]pyrimidine-2-carboxylate(4 g, 6.07 mmol) in THF (40 mL) was added 1N NaOH (6.07 mL, 6.07 mmol)and the resulting mixture was stirred at rt for 16 h. At this point theLCMS indicated about 70% conversion, so additional 1N NaOH (2.5 mL, 2.5mmol) was added and the mixture was stirred for another 2 h. At thispoint LCMS indicated progression of reaction (˜90% conversion) alongwith small amount of di-acid. Water (20 mL) was then added to thereaction mixture and it was acidified with 1N HCl (10 mL). This aqueoussolution was extracted with ether (2×100 mL), washed with brine (50 mL),dried (Na₂SO₄), filtered and concentrated in vacuo to afford6-((S)-1-(tert-butoxy)-2-ethoxy-2-oxoethyl)-7-(8-fluoro-5-methylchroman-6-yl)-5-methylpyrazolo[1,5-a]pyrimidine-2-carboxylicacid (2.7 g, 5.41 mmol, 89% yield) as off-white solid. 1H NMR (500 MHz,CDCl₃) δ 7.21 (s, 1H), 6.85 (d, J=10.7 Hz, 1H), 5.00 (s, 1H), 4.36 (t,J=4.4 Hz, 2H), 4.19-4.12 (m, 2H), 2.81 (s, 3H), 2.80-2.74 (m, 2H), 2.20(dd, J=6.3, 4.1 Hz, 2H), 1.83 (s, 3H), 1.24-1.20 (m, 3H), 1.18 (s, 9H).LCMS (M+H)=500.4.

(2S)-ethyl2-tert-butoxy-2-(7-(8-fluoro-5-methylchroman-6-yl)-5-methyl-2-((2-(trimethylsilyl)ethoxy)carbonylamino)pyrazolo[1,5-a]pyrimidin-6-yl)acetate

A mixture of6-((S)-1-(tert-butoxy)-2-ethoxy-2-oxoethyl)-7-(8-fluoro-5-methylchroman-6-yl)-5-methylpyrazolo[1,5-a]pyrimidine-2-carboxylicacid (3.40 g, 5.79 mmol), diphenylphosphoryl azide (1.50 mL, 6.94 mmol),2-(trimethylsilyl)ethanol (1.66 mL, 11.6 mmol), triethylamine (0.968 mL,6.94 mmol) in toluene (100 mL) was refluxed for 16 h. It was thenconcentrated in vacuo. The residue was purified by biotage eluting with20% EtOAc/hexane to isolate 2.5 g (70%) of (2S)-ethyl2-tert-butoxy-2-(7-(8-fluoro-5-methylchroman-6-yl)-5-methyl-2-((2-(trimethylsilyl)ethoxy)carbonylamino)pyrazolo[1,5-a]pyrimidin-6-yl)acetateas off-white solid. 1H NMR (500 MHz, CDCl₃) δ 7.25 (s, 1H), 6.89 (s,1H), 6.87 (d, J=6.9 Hz, 1H), 4.90 (s, 1H), 4.34 (m, 2H), 4.30 (m, 2H),4.13 (d, J=7.1 Hz, 2H), 2.84-2.63 (m, 5H), 2.18 (m, 2H), 1.84 (s, 3H),1.20 (t, J=7.1 Hz, 3H), 1.17 (s, 9H), 1.05 (m, 2H), 0.07 (s, 9H). LCMS(M+H)=615.4.

(2S)-ethyl2-(2-amino-7-(8-fluoro-5-methylchroman-6-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-tert-butoxyacetate

A mixture of (2S)-ethyl2-tert-butoxy-2-(7-(8-fluoro-5-methylchroman-6-yl)-5-methyl-2-((2-(trimethylsilyl)ethoxy)carbonylamino)pyrazolo[1,5-a]pyrimidin-6-yl)acetate(2.3 g, 3.74 mmol), 1M TBAF (4.49 mL, 4.49 mmol) in THF (20 mL) wasstirred at rt for 3 h. It was then concentrated, diluted with water, andextracted with EtOAc. The organic phase was washed with water, driedover MgSO₄, filtered and concentrated to yield 1.5 g (85%) of (2S)-ethyl2-(2-amino-7-(8-fluoro-5-methylchroman-6-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetateas a oil which solidified upon standing for one day. 1H NMR (500 MHz,CDCl₃) δ 6.87 (d, J=10.56 Hz, 1H), 5.88 (s, 1H), 4.85 (s, 1H), 4.33 (t,J=5.04 Hz, 2H), 4.08-4.14 (m, 4H), 2.76 (t, J=6.38 Hz, 2H), 2.71 (s,3H), 2.13-2.21 (m, 2H), 1.87 (s, 3H), 1.20 (t, J=7.17 Hz, 3H), 1.16 (s,9H). LCMS (M+H)=471.36.

Example 1(2S)-2-(2-amino-7-(8-fluoro-5-methylchroman-6-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-tert-butoxyaceticacid

A mixture of (2S)-ethyl2-(2-amino-7-(8-fluoro-5-methylchroman-6-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate(1.20 g, 2.55 mmol), 1N NaOH (3.83 mL, 3.83 mmol) in EtOH (20 mL) wasstirred at rt for 16 h. LCMS indicated a small amount of startingmaterial remaining, therefore, the reaction mixture washeated at 60° C.for 2 h. At this time, LCMS indicated that the ester hydrolysis wascomplete. The reaction mixture was then concentrated in vacuo, and theresidue was adjusted to pH=4 using 1N HCl. A white precipitate formedand was collected by filtration, washed with water, and dried in vacuoto obtain(2S)-2-(2-amino-7-(8-fluoro-5-methylchroman-6-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)aceticacid (1.06 g, 2.16 mmol, 85% yield) as a off-white solid. 1H NMR (500MHz, CDCl₃) δ 6.90 (d, J=10.56 Hz, 1H), 5.91 (s, 1H), 4.97 (s, 1H),4.26-4.35 (m, 2H), 2.74 (m, 2H), 2.65 (s, 3H), 2.11-2.18 (m, 2H), 1.95(s, 3H), 1.21 (s, 9H). LCMS (M+H)=443.23.

General Procedure for the Preparation Amides and Carbamates:

A mixture of2S)-2-(2-amino-7-(8-fluoro-5-methylchroman-6-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)aceticacid (22 mg, 0.050 mmol), 3-cyclopentylpropanoyl chloride (8.79 mg,0.055 mmol), Hunig's Base (0.026 mL, 0.15 mmol) in THF (2 mL) wasstirred at rt for 16 h. It was then concentrated in vacuo and purifiedby prep HPLC (TFA/MeOH), the desired fractions were combined andadjusted to pH=6 using a few drops of 1N NaOH. The residue was thenacidified to pH=4 using a few drops of 1N HCl. This solution wasextracted with EtOAc. The organic phase was dried over MgSO₄, filtered,and concentrated in vacuo to obtain (10 mg, 35%) of(2S)-2-tert-butoxy-2-(2-(3-cyclopentylpropanamido)-7-(8-fluoro-5-methylchroman-6-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)aceticacid as white solid.

Example 2(2S)-2-tert-butoxy-2-(2-(3-cyclopentylpropanamido)-7-(8-fluoro-5-methylchroman-6-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)aceticacid

1H NMR (500 MHz, CDCl₃) δ=7.95 (br. s., 1H), 7.16 (s, 1H), 6.89 (d,J=10.4 Hz, 1H), 5.02 (s, 1H), 4.43-4.26 (m, 2H), 2.75 (d, J=3.0 Hz, 2H),2.71 (s, 3H), 2.35 (t, J=7.3 Hz, 2H), 2.20-2.13 (m, 2H), 1.92 (s, 3H),1.85-0.90 (m, 11H), 1.22 (s, 9H). LCMS (M+H)=567.38.

The following compounds were prepared according to the general proceduredescribed above using Example 1 and appropriate acylating reagent.

Example 3(2S)-2-tert-butoxy-2-(7-(8-fluoro-5-methylchroman-6-yl)-2-(2-(4-fluorophenyl)acetamido)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)aceticacid

¹H NMR (400 MHz, CDCl₃) δ 8.37 (s, 1H), 7.35-7.22 (m, 2H), 7.17 (s, 1H),7.11-6.98 (m, 2H), 6.84 (d, J=10.5 Hz, 1H), 5.00 (s, 1H), 4.39-4.22 (m,2H), 3.68 (s, 2H), 2.81-2.63 (m, 5H), 2.21-2.07 (m, 2H), 1.88 (s, 3H),1.24-1.16 (s, 9H). LCMS (M+H)=579.4.

Example 4(2S)-2-tert-butoxy-2-(7-(8-fluoro-5-methylchroman-6-yl)-5-methyl-2-(2-phenylacetamido)pyrazolo[1,5-a]pyrimidin-6-yl)aceticacid

¹H NMR (500 MHz, CDCl₃) δ 8.39 (s, 1H), 7.40-7.34 (m, 2H), 7.33-7.27 (m,3H), 7.19 (s, 1H), 6.87-6.80 (m, 1H), 4.98 (s, 1H), 4.35-4.25 (m, 2H),3.73 (s, 2H), 2.75-2.66 (m, 5H), 2.20-2.08 (m, 2H), 1.87 (s, 3H), 1.20(s, 9H). LCMS (M+H)=561.30.

Example 5(2S)-2-tert-butoxy-2-(7-(8-fluoro-5-methylchroman-6-yl)-2-(3-fluorobenzamido)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)aceticacid

¹H NMR (500 MHz, CDCl₃) δ 8.92 (s, 1H), 7.64 (d, J=7.9 Hz, 2H),7.49-7.39 (m, 1H), 7.28-7.20 (m, 2H), 6.83 (d, J=10.1 Hz, 1H), 5.06-4.91(m, 1H), 4.41-4.22 (m, 2H), 2.73 (s, 5H), 2.15 (m, 2H), 1.85 (s, 3H),1.19 (s, 9H). LCMS (M+H)=565.40.

Example 6(2S)-2-tert-butoxy-2-(7-(8-fluoro-5-methylchroman-6-yl)-2-(3-methoxybenzamido)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)aceticacid

¹H NMR (500 MHz, CDCl₃) δ 8.76 (s, 1H), 7.47 (br. s., 1H), 7.44-7.39 (m,1H), 7.39-7.34 (m, 1H), 7.32 (s, 1H), 7.13-7.07 (m, 1H), 6.88 (d, J=10.6Hz, 1H), 5.03 (s, 1H), 4.33 (m, 2H), 3.87 (s, 3H), 2.74 (m, 5H), 1.90(s, 3H), 2.22-2.10 (m, 2H), 1.22 (s, 9H). LCMS (M+H)=577.36.

Example 7(2S)-2-(2-(3-(benzyloxy)benzamido)-7-(8-fluoro-5-methylchroman-6-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-tert-butoxyaceticacid

¹H NMR (500 MHz, CDCl₃) δ 8.70 (s, 1H), 7.57 (br. s., 1H), 7.51-7.34 (m,7H), 7.32 (s, 1H), 7.21-7.13 (m, 1H), 6.96-6.86 (m, 1H), 5.14 (s, 2H),5.04 (s, 1H), 4.33 (m, 2H), 2.74 (m, 5H), 2.24-2.11 (m, 2H), 1.92 (s,3H), 1.23 (s, 9H). LCMS (M+H)=653.31.

Example 8(2S)-2-tert-butoxy-2-(2-(3-cyanobenzamido)-7-(8-fluoro-5-methylchroman-6-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)aceticacid

¹H NMR (500 MHz, CDCl₃) δ 9.50 (br. s., 1H), 8.26 (br. s., 1H), 8.16 (d,J=7.3 Hz, 1H), 7.85 (d, J=7.3 Hz, 1H), 7.69-7.59 (m, 1H), 7.36 (br. s.,1H), 6.85 (d, J=10.4 Hz, 1H), 5.04 (br. s., 1H), 4.33 (br. s., 2H), 2.77(br. s., 5H), 2.25-2.09 (m, 2H), 1.91 (br. s., 3H), 1.22 (br. s., 9H).LCMS (M+H)=572.27.

Example 9(2S)-2-(2-(2-(benzyloxy)acetamido)-7-(8-fluoro-5-methylchroman-6-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-tert-butoxyaceticacid

¹H NMR (500 MHz, CDCl₃) δ 9.08 (s, 1H), 7.44-7.32 (m, 5H), 7.21 (s, 1H),6.89 (d, J=10.6 Hz, 1H), 5.03 (s, 1H), 4.63 (s, 2H), 4.38-4.29 (m, 2H),4.12 (s, 2H), 2.74 (m, 5H), 2.23-2.12 (m, 2H), 1.90 (s, 3H), 1.22 (s,9H). LCMS (M+H)=591.32.

Example 10(2S)-2-tert-butoxy-2-(2-(3,4-dimethylbenzamido)-7-(8-fluoro-5-methylchroman-6-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)aceticacid

¹H NMR (500 MHz, CDCl₃) δ 8.86 (s, 1H), 7.70 (s, 1H), 7.62 (d, J=7.9 Hz,1H), 7.34 (s, 1H), 7.23 (d, J=7.9 Hz, 1H), 6.89 (d, J=10.6 Hz, 1H), 5.03(s, 1H), 4.38-4.27 (m, 2H), 2.74 (s, 5H), 2.33 (d, J=3.5 Hz, 6H),2.21-2.11 (m, 2H), 1.91 (s, 3H), 1.22 (s, 9H). LCMS (M+H)=575.33.

Example 11(2S)-2-tert-butoxy-2-(2-(3-tert-butyl-1-methyl-1H-pyrazole-5-carboxamido)-7-(8-fluoro-5-methylchroman-6-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)aceticacid

¹H NMR (500 MHz, CDCl₃) δ 8.99 (s, 1H), 7.27 (s, 1H), 6.87 (d, J=10.4Hz, 1H), 6.58 (s, 1H), 5.03 (s, 1H), 4.36-4.30 (m, 2H), 4.20 (s, 3H),2.76 (s, 5H), 2.20-2.13 (m, 2H), 1.91 (s, 3H), 1.30 (s, 9H), 1.22 (s,9H). LCMS (M+H)=607.36.

Example 12(2S)-2-tert-butoxy-2-(7-(8-fluoro-5-methylchroman-6-yl)-5-methyl-2-(4-phenylbutanamido)pyrazolo[1,5-a]pyrimidin-6-yl)aceticacid

¹H NMR (500 MHz, CDCl₃) δ 8.30 (br. s., 1H), 7.29 (s, 2H), 7.23-7.15 (m,4H), 6.90-6.83 (m, 1H), 5.01 (s, 1H), 4.35-4.28 (m, 2H), 2.72 (m, 7H),2.39-2.33 (m, 2H), 2.19-2.12 (m, 2H), 2.10-2.03 (m, 2H), 1.90 (s, 3H),1.21 (s, 9H). LCMS (M+H)=589.30.

Example 13(2S)-2-tert-butoxy-2-(7-(8-fluoro-5-methylchroman-6-yl)-2-(2-((2R,5S)-2-isopropyl-5-methylcyclohexyloxy)acetamido)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)aceticacid

¹H NMR (400 MHz, CDCl₃) δ 9.00 (br. s., 1H), 7.22 (s, 1H), 6.98-6.85 (m,1H), 5.03 (s, 1H), 4.34 (br. s., 2H), 4.26-4.15 (m, 1H), 4.09-4.01 (m,1H), 3.27-3.14 (m, 1H), 2.84-2.66 (m, 5H), 2.17 (br. s., 3H), 2.04 (d,J=11.3 Hz, 1H), 1.91 (br. s., 3H), 1.67 (br. s., 2H), 1.45-1.13 (m,11H), 1.05-0.83 (m, 9H), 0.81-0.72 (m, 3H). LCMS (M+H)=639.49.

Example 14(2S)-2-tert-butoxy-2-(2-(3-ethoxybenzamido)-7-(8-fluoro-5-methylchroman-6-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)aceticacid

¹H NMR (500 MHz, DMSO-d6) δ 11.26 (s, 1H), 7.59 (d, J=1.5 Hz, 2H),7.44-7.30 (m, 1H), 7.14-7.03 (m, 3H), 4.73 (s, 1H), 4.31-4.20 (m, 2H),4.10 (q, J=7.0 Hz, 2H), 2.68 (s, 5H), 2.13-1.96 (m, 2H), 1.82 (s, 3H),1.35 (s, 3H), 1.07 (s, 9H). LCMS (M+H)=591.5.

Example 15(2S)-2-tert-butoxy-2-(2-(3,4-dimethoxybenzamido)-7-(8-fluoro-5-methylchroman-6-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)aceticacid

¹H NMR (500 MHz, DMSO-d₆) δ 11.12 (s, 1H), 7.77-7.63 (m, 2H), 7.08 (d,J=11.3 Hz, 1H), 7.06-7.02 (m, 2H), 4.73 (br. s., 1H), 4.26 (d, J=3.1 Hz,2H), 3.83 (s, 6H), 2.79-2.63 (m, 5H), 2.14-1.97 (m, 2H), 1.82 (s, 3H),1.07 (s, 9H). LCMS (M+H)=607.44.

Example 16(2S)-2-tert-butoxy-2-(7-(8-fluoro-5-methylchroman-6-yl)-5-methyl-2-(3-phenylpropanamido)pyrazolo[1,5-a]pyrimidin-6-yl)aceticacid

¹H NMR (500 MHz, DMSO-d₆) δ 10.94 (s, 1H), 7.30-7.25 (m, 2H), 7.24-7.20(m, 2H), 7.20-7.15 (m, 1H), 7.03 (d, J=11.3 Hz, 1H), 6.84 (s, 1H), 4.72(br. s., 1H), 4.25 (d, J=3.1 Hz, 2H), 2.90-2.83 (m, 2H), 2.74-2.59 (m,7H), 2.12-1.95 (m, 2H), 1.78 (s, 3H), 1.07 (s, 9H). LCMS (M+H)=575.4.

Example 17(2S)-2-tert-butoxy-2-(7-(8-fluoro-5-methylchroman-6-yl)-2-hexanamido-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)aceticacid

¹H NMR (500 MHz, DMSO-d₆) δ 10.86 (s, 1H), 7.04 (d, J=11.0 Hz, 1H), 6.84(s, 1H), 4.77-4.66 (m, 1H), 4.31-4.19 (m, 2H), 2.65 (s, 5H), 2.35-2.24(m, 2H), 2.11-1.97 (m, 2H), 1.78 (s, 3H), 1.61-1.49 (m, 2H), 1.27 (d,J=7.6 Hz, 4H), 1.07 (s, 9H), 0.86 (t, J=7.0 Hz, 3H). LCMS (M+H)=541.47.

Example 18(2S)-2-tert-butoxy-2-(7-(8-fluoro-5-methylchroman-6-yl)-5-methyl-2-(9-oxo-9H-fluorene-3-carboxamido)pyrazolo[1,5-a]pyrimidin-6-yl)aceticacid

¹H NMR (500 MHz, DMSO-d₆) δ 11.80 (s, 1H), 7.76-7.65 (m, 3H), 7.62-7.52(m, 2H), 7.47-7.37 (m, 2H), 7.13 (s, 1H), 7.09 (d, J=11.3 Hz, 1H), 4.79(s, 1H), 4.31-4.12 (m, 2H), 2.71 (s, 3H), 2.73-2.56 (m, 2H), 2.10-1.93(m, 2H), 1.81 (s, 3H), 1.09 (s, 9H). LCMS (M+H)=649.48.

Example 19(2S)-2-tert-butoxy-2-(2-(2-ethoxybenzamido)-7-(8-fluoro-5-methylchroman-6-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)aceticacid

¹H NMR (500 MHz, DMSO-d₆) δ 10.81 (s, 1H), 7.73-7.68 (m, 1H), 7.50-7.45(m, 1H), 7.13 (d, J=8.2 Hz, 1H), 7.06-7.00 (m, 2H), 6.92 (s, 1H), 4.75(br. s., 1H), 4.29-4.21 (m, 2H), 4.14 (q, J=7.0 Hz, 2H), 2.78-2.59 (m,5H), 2.13-1.97 (m, 2H), 1.80 (s, 3H), 1.32-1.27 (m, 3H), 1.08 (s, 9H).LCMS (M+H)=591.45.

Example 20(2S)-2-tert-butoxy-2-(2-(7,7-dimethyloctanamido)-7-(8-fluoro-5-methylchroman-6-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)aceticacid

¹H NMR (500 MHz, DMSO-d₆) δ 10.33-10.17 (m, 1H), 7.08 (s, 1H), 6.93-6.86(m, 1H), 4.74 (s, 1H), 4.31-4.19 (m, 2H), 2.74-2.61 (m, 5H), 2.12-1.96(m, 2H), 1.79 (br. s., 3H), 1.77-1.68 (m, 1H), 1.48-1.36 (m, 1H),1.27-1.09 (m, 7H), 1.07 (s, 9H), 0.94 (m, 1H), 0.89-0.67 (m, 9H). LCMS(M+H)=597.57.

Example 21(2S)-2-tert-butoxy-2-(2-(2-cyclopentylacetamido)-7-(8-fluoro-5-methylchroman-6-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)aceticacid

¹H NMR (500 MHz, DMSO-d₆) δ 10.85 (s, 1H), 7.04 (d, J=11.3 Hz, 1H), 6.84(s, 1H), 4.71 (s, 1H), 4.25 (br. s., 2H), 2.74-2.61 (m, 5H), 2.34-2.27(m, 2H), 2.20 (dt, J=15.2, 7.5 Hz, 1H), 2.12-1.96 (m, 2H), 1.79 (s, 3H),1.75-1.67 (m, 2H), 1.63-1.54 (m, 2H), 1.54-1.43 (m, 2H), 1.18-1.09 (m,2H), 1.07 (s, 9H). LCMS (M+H)=553.43.

Example 22(2S)-2-tert-butoxy-2-(2-(2,2-difluorobenzo[d][1,3]-dioxole-5-carboxamido)-7-(8-fluoro-5-methylchroman-6-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)aceticacid

¹H NMR (500 MHz, DMSO-d₆) δ 11.37 (s, 1H), 8.05 (d, J=1.8 Hz, 1H), 7.94(dd, J=8.5, 1.8 Hz, 1H), 7.53 (d, J=8.5 Hz, 1H), 7.10 (d, J=11.0 Hz,1H), 7.04 (s, 1H), 4.77 (s, 1H), 4.30-4.22 (m, 2H), 2.74-2.63 (m, 5H),2.13-1.99 (m, 2H), 1.81 (s, 3H), 1.08 (s, 9H). LCMS (M+H)=627.40.

Example 23(2S)-2-tert-butoxy-2-(7-(8-fluoro-5-methylchroman-6-yl)-2-(3-(4-methoxyphenyl)propanamido)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)aceticacid

¹H NMR (500 MHz, DMSO-d₆) δ 10.90 (s, 1H), 7.13 (d, J=8.5 Hz, 2H), 7.02(d, J=11.3 Hz, 1H), 6.87-6.75 (m, 3H), 4.69 (s, 1H), 4.35-4.11 (m, 2H),3.71 (s, 3H), 2.81 (t, J=7.6 Hz, 2H), 2.73-2.61 (m, 5H), 2.61-2.55 (m,2H), 2.11-1.98 (m, 2H), 1.78 (s, 3H), 1.06 (s, 9H). LCMS (M+H)=605.46.

Example 24(2S)-2-tert-butoxy-2-(7-(8-fluoro-5-methylchroman-6-yl)-5-methyl-2-(3-methyl-2-phenoxybutanamido)pyrazolo[1,5-a]pyrimidin-6-yl)aceticacid

A mixture of two diastereomers. LCMS (M+H)=619.50.

Example 25(2S)-2-tert-butoxy-2-(2-(2-cyclohexylacetamido)-7-(8-fluoro-5-methylchroman-6-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)aceticacid

¹H NMR (500 MHz, DMSO-d₆) δ 10.84 (s, 1H), 7.03 (d, J=11.3 Hz, 1H), 6.84(s, 1H), 4.62 (s, 1H), 4.25 (br. s., 2H), 2.74-2.61 (m, 5H), 2.22-2.16(m, 2H), 2.11-1.98 (m, 2H), 1.79 (s, 3H), 1.77-1.71 (m, 1H), 1.69-1.54(m, 5H), 1.27-1.08 (m, 3H), 1.06 (s, 9H), 0.97-0.86 (m, 2H). LCMS(M+H)=567.49.

Example 26(2S)-2-tert-butoxy-2-(2-(2-(3,4-dichlorophenyl)acetamido)-7-(8-fluoro-5-methylchroman-6-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)aceticacid

¹H NMR (500 MHz, DMSO-d₆) δ 11.24 (s, 1H), 7.63-7.53 (m, 2H), 7.29 (dd,J=8.2, 1.8 Hz, 1H), 7.06 (d, J=11.3 Hz, 1H), 6.88-6.73 (m, 1H), 4.78 (s,1H), 4.35-4.18 (m, 2H), 3.73-3.61 (m, 2H), 2.79-2.62 (m, 5H), 2.18-1.96(m, 2H), 1.80 (s, 3H), 1.08 (s, 9H). LCMS (M+H)=629.39.

Example 27(2S)-2-tert-butoxy-2-(7-(8-fluoro-5-methylchroman-6-yl)-5-methyl-2-(4-phenoxybutanamido)pyrazolo[1,5-a]pyrimidin-6-yl)aceticacid

¹H NMR (500 MHz, DMSO-d₆) δ 10.88 (s, 1H), 7.27 (t, J=8.1 Hz, 2H), 6.97(d, J=11.3 Hz, 1H), 6.94-6.88 (m, 3H), 6.79 (s, 1H), 4.51-4.44 (m, 1H),4.23 (br. s., 2H), 3.97 (t, J=6.4 Hz, 2H), 2.72-2.61 (m, 5H), 2.50-2.44(m, 2H), 2.03-1.97 (m, 4H), 1.84 (s, 3H), 1.08-0.98 (m, 9H). LCMS(M+H)=605.47.

Example 28(2S)-2-tert-butoxy-2-(2-(3-cyclohexylpropanamido)-7-(8-fluoro-5-methylchroman-6-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)aceticacid

LCMS (M+H)=581.51.

Example 29(2S)-2-tert-butoxy-2-(7-(8-fluoro-5-methylchroman-6-yl)-5-methyl-2-(3,4,5-trimethoxybenzamido)pyrazolo[1,5-a]pyrimidin-6-yl)aceticacid

¹H NMR (500 MHz, DMSO-d₆) δ 11.24 (s, 1H), 7.42 (s, 2H), 7.10 (d, J=11.0Hz, 1H), 7.07 (s, 1H), 4.74 (s, 1H), 4.35-4.19 (m, 2H), 3.85 (s, 6H),3.73 (s, 3H), 2.73-2.63 (m, 5H), 2.12-1.97 (m, 2H), 1.82 (s, 3H), 1.07(s, 9H) LCMS (M+H)=637.5.

Example 30(2S)-2-tert-butoxy-2-(2-(2-(1,3-dioxoisoindolin-2-yl)acetamido)-7-(8-fluoro-5-methylchroman-6-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)aceticacid

¹H NMR (500 MHz, DMSO-d₆) δ 11.46 (s, 1H), 7.98-7.88 (m, 4H), 7.08 (d,J=11.0 Hz, 1H), 6.76 (s, 1H), 4.79 (s, 1H), 4.42 (s, 2H), 4.26 (br. s.,2H), 2.74-2.63 (m, 5H), 2.12-1.99 (m, 2H), 1.79 (s, 3H), 1.08 (s, 9H).LCMS (M+H)=630.4.

Example 31(2S)-2-(2-(2-(1H-indol-3-yl)-2-oxoacetamido)-7-(8-fluoro-5-methylchroman-6-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-tert-butoxyaceticacid

¹H NMR (500 MHz, DMSO-d₆) δ 12.37 (br. s., 1H), 11.24 (br. s., 1H), 8.62(s, 1H), 8.24-8.17 (m, 1H), 7.60-7.52 (m, 1H), 7.28 (ddd, J=7.2, 5.4,1.4 Hz, 2H), 7.07 (d, J=11.0 Hz, 1H), 7.02 (s, 1H), 4.80 (s, 1H), 4.26(t, J=5.0 Hz, 2H), 2.70 (m, 5H), 2.14-1.98 (m, 2H), 1.81 (s, 3H), 1.09(s, 9H). LCMS (M+H)=614.43.

Example 32(2S)-2-(tert-butoxy)-2-(7-(8-fluoro-5-methylchroman-6-yl)-5-methyl-2-(((p-tolyloxy)carbonyl)amino)pyrazolo[1,5-a]pyrimidin-6-yl)aceticacid

LCMS (M+H)=577.29.

Example 33(2S)-2-(2-(((benzyloxy)carbonyl)amino)-7-(8-fluoro-5-methylchroman-6-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)aceticacid

LCMS (M+H)=577.3.

Example 34(2S)-2-(tert-butoxy)-2-(2-((butoxycarbonyl)amino)-7-(8-fluoro-5-methylchroman-6-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)aceticacid

LCMS (M+H)=543.31.

Example 35(2S)-2-(tert-butoxy)-2-(7-(8-fluoro-5-methylchroman-6-yl)-5-methyl-2-(((neopentyloxy)carbonyl)amino)pyrazolo[1,5-a]pyrimidin-6-yl)aceticacid

LCMS (M+H)=557.22.

Prepared according to the above procedure for Example 1.

Example 36(2S)-2-(tert-butoxy)-2-(7-(8-fluoro-5-methylchroman-6-yl)-5-methyl-2-(((2-(trimethylsilyl)ethoxy)carbonyl)amino)pyrazolo[1,5-a]pyrimidin-6-yl)aceticacid

LCMS (M+H)=587.6.

Example 37(2S)-2-(tert-butoxy)-2-(7-(8-fluoro-5-methylchroman-6-yl)-5-methyl-2-(3-(p-tolyl)ureido)pyrazolo[1,5-a]pyrimidin-6-yl)aceticacid

A mixture of Example 1 (22 mg, 0.050 mmol), 1-isocyanato-4-methylbenzene(7.28 mg, 0.055 mmol), Hunig's base (0.026 mL, 0.149 mmol) in THF (2 mL)was stirred at rt for 16 h. It was then concentrated and purified byprep HPLC (TFA/MeOH). The fractions were combined and adjusted pH=6using 1N NaOH. The residue was adjusted pH=3-4 by adding 1-2 drops of 1NHCl. It was then extracted with EtOAc, dried, filtered and concentratedto obtained Example (18 mg, 60%) as light yellow solid. LCMS(M+H)=576.31.

Example 38(2S)-2-(2-(benzylamino)-7-(8-fluoro-5-methylchroman-6-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)aceticacid

A mixture of Example 1 (20 mg, 0.045 mmol), benzaldehyde (5.28 mg, 0.050mmol), acetic acid (0.013 mL, 0.226 mmol) and NaCNBH₃ (14.20 mg, 0.226mmol) in MeOH (2 mL) was stirred at rt for 16 h. It was thenconcentrated and purified by prep HPLC to isolate Example 38 (15 mg,59%) as yellow solid. NMR-CDCl₃, LC-MS: consistent with the desiredproduct. ¹H NMR (500 MHz, CDCl₃) δ 7.33 (d, J=4.4 Hz, 5H), 6.85 (d,J=10.6 Hz, 1H), 5.91 (s, 1H), 4.98 (s, 1H), 4.40 (s, 2H), 4.37-4.26 (m,2H), 2.83-2.58 (m, 5H), 2.25-2.09 (m, 2H), 1.92 (s, 3H), 1.20 (s, 9H).LCMS (M+H)=533.38.

The following compounds were prepared according to the general proceduredescribed above using appropriate aldehyde.

Example 39(2S)-2-(tert-butoxy)-2-(7-(8-fluoro-5-methylchroman-6-yl)-5-methyl-2-(phenethylamino)pyrazolo[1,5-a]pyrimidin-6-yl)aceticacid

LCMS (M+H)=547.27.

Example 40(2S)-2-(tert-butoxy)-2-(7-(8-fluoro-5-methylchroman-6-yl)-5-methyl-2-((4-methylphenethyl)amino)pyrazolo[1,5-a]pyrimidin-6-yl)aceticacid

LCMS (M+H)=561.19.

Example 41(2S)-2-(tert-butoxy)-2-(7-(8-fluoro-5-methylchroman-6-yl)-5-methyl-2-((3-phenylpropyl)amino)pyrazolo[1,5-a]pyrimidin-6-yl)aceticacid

LCMS (M+H)=561.33.

Example 42(2S)-2-(tert-butoxy)-2-(2-((3-cyclopentylpropyl)amino)-7-(8-fluoro-5-methylchroman-6-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)aceticacid

LCMS (M+H)=553.25.

Example 43(2S)-2-(tert-butoxy)-2-(7-(8-fluoro-5-methylchroman-6-yl)-2-(isopentylamino)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)aceticacid

LCMS (M+H)=513.15.

Example 44(2S)-2-(tert-butoxy)-2-(2-(diisopentylamino)-7-(8-fluoro-5-methylchroman-6-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)aceticacid

LCMS (M+H)=583.13.

Example 45(2S)-2-(tert-butoxy)-2-(2-((3,3-dimethylbutyl)amino)-7-(8-fluoro-5-methylchroman-6-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)aceticacid

LCMS (M+H)=527.05.

Example 46(2S)-2-(2-(bis(3,3-dimethylbutyl)amino)-7-(8-fluoro-5-methylchroman-6-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)aceticacid

LCMS (M+H)=611.14.

Example 47(2S)-2-(tert-butoxy)-2-(7-(8-fluoro-5-methylchroman-6-yl)-5-methyl-2-((3,5,5-trimethylhexyl)amino)pyrazolo[1,5-a]pyrimidin-6-yl)aceticacid

LCMS (M+H)=569.25.

Example 48(2S)-2-(tert-butoxy)-2-(7-(8-fluoro-5-methylchroman-6-yl)-5-methyl-2-((3,3,3-trifluoropropyl)amino)pyrazolo[1,5-a]pyrimidin-6-yl)aceticacid

LCMS (M+H)=539.07.

Example 49(2S)-2-(tert-butoxy)-2-(2-(cyclopentylamino)-7-(8-fluoro-5-methylchroman-6-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)aceticacid

511.23.

Example 50(2S)-2-(tert-butoxy)-2-(7-(8-fluoro-5-methylchroman-6-yl)-5-methyl-2-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidin-6-yl)aceticacid

LCMS (M+H)=511.3.

Example 51(2S)-2-(tert-butoxy)-2-(7-(8-fluoro-5-methylchroman-6-yl)-5-methyl-2-(pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-6-yl)aceticacid

LCMS (M+H)=497.28.

Example 52(2S)-2-(tert-butoxy)-2-(2-((3-cyclopentylpropyl)(methyl)amino)-7-(8-fluoro-5-methylchroman-6-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)aceticacid

A mixture of example 1 (20 mg, 0.045 mmol), 3-cyclopentylpropanal (6.84mg, 0.054 mmol), NaCNBH₃ (14.20 mg, 0.226 mmol), acetic acid (0.013 mL,0.226 mmol) in MeOH (2 mL) was stirred at rt for 2 h. Then addedparaformaldehyde (13.57 mg, 0.136 mmol)/H₂O and stirred at rt foranother 2 h. It was then concentrated and purified by prep HPLC to giveExample 52 (10 mg, 37%) as yellow solid. LCMS (M+H)=567.26.

It will be evident to one skilled in the art that the present disclosureis not limited to the foregoing illustrative examples, and that it canbe embodied in other specific forms without departing from the essentialattributes thereof. It is therefore desired that the examples beconsidered in all respects as illustrative and not restrictive,reference being made to the appended claims, rather than to theforegoing examples, and all changes which come within the meaning andrange of equivalency of the claims are therefore intended to be embracedtherein.

We claim:
 1. A compound of Formula I

where: R¹ is N(R⁶)(R⁷); R² is hydrogen, halo, or alkyl; R³ is alkyl,cycloalkyl, or Ar¹; R⁴ is alkyl or haloalkyl; R⁵ is alkyl; R⁶ ishydrogen, alkyl, haloalkyl, (cycloalkyl)alkyl, (Ar²)alkyl, cycloalkyl,(alkyl)cycloalkyl, (Ar²)cycloalkyl, (alkyl)CO, (haloalkyl)CO,((cycloalkyl)alkyl)CO, (Ar²)CO, ((Ar²)alkyl)CO, ((Ar²)alkyl)OCO,((Ar²)alkyl)NHCO, or ((Ar²)alkyl)COCO; or R⁶ is((trialkylsilyl)alkyl)OCO, (benzyloxy)alkylCO, (phenoxyalkyl)CO,(isoindolinedionyl)alkyl)CO, (((dialkyl)cycloalkoxy)alkyl)CO,(phenoxyalkyl)CO, or (dihalobenzodioxolyl)CO; R⁷ is hydrogen or alkyl;or N(R⁶)(R⁷) taken together is azetidinyl, pyrrolidinyl, piperidinyl,piperazinyl, morpholinyl, homopiperidinyl, homopiperazinyl, orhomomorpholinyl, and is substituted with 0-3 substituents selected fromhalo, alkyl, haloalkyl, hydroxy, alkoxy, or haloalkoxy; and Ar¹ isphenyl, pyridinyl, indanyl, naphthyl, tetrahydronaphthalenyl,benzofuranyl, dihydrobenzofuranyl, benzodioxyl, chromanyl, isochromanyl,benzodioxanyl, quinolinyl, tetrahydroquinolinyl, isoquinolinyl,tetrahydroisoquinolinyl, dihydrobenzoxazinyl, indolyl, dihydroindolyl,benzthiazolyl, or benzothiazolyl, and is substituted with 0-3substituents selected from halo, cyano, alkyl, haloalkyl, cycloalkyl,halocycloalkyl, hydroxy, alkoxy, haloalkoxy, phenoxy, benzyloxy,thioalkyl, and acetamido; or Ar¹ is

Ar² is phenyl, biphenyl, pyrazolyl, indolyl, or fluorenonyl, and issubstituted with 0-3 substituents selected from cyano, halo, alkyl,haloalkyl, cycloalkyl, halocycloalkyl, alkoxy, benzyloxy, andhaloalkoxy; or a pharmaceutically acceptable salt thereof.
 2. A compoundof claim 1 where: R¹ is N(R⁶)(R⁷); R² is hydrogen; R³ is Ar¹; R⁴ isalkyl; R⁵ is alkyl; R⁶ is hydrogen, alkyl, haloalkyl, (cycloalkyl)alkyl,(Ar²)alkyl, cycloalkyl, (alkyl)CO, ((cycloalkyl)alkyl)CO, (Ar²)CO,((Ar²)alkyl)CO, ((Ar²)alkyl)OCO, ((Ar²)alkyl)NHCO, or ((Ar²)alkyl)COCO;or R⁶ is ((trialkylsilyl)alkyl)OCO, (benzyloxy)alkylCO,(phenoxyalkyl)CO, (isoindolinedionyl)alkyl)CO,(((dialkyl)cycloalkoxy)alkyl)CO, (phenoxyalkyl)CO, or(dihalobenzodioxolyl)CO; R⁷ is hydrogen or alkyl; or where N(R⁶)(R⁷)taken together is pyrrolidinyl or piperidinyl, and is substituted with0-3 substituents selected from halo, alkyl, haloalkyl, hydroxy, alkoxy,and haloalkoxy; Ar¹ is chromanyl substituted with 0-3 substituentsselected from halo, cyano, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, hydroxy, alkoxy, haloalkoxy, phenoxy, benzyloxy, thioalkyl,and acetamido; and Ar² is phenyl, pyrazolyl, indolyl, or fluorenonyl,and is substituted with 0-3 substituents selected from cyano, halo,alkyl, haloalkyl, cycloalkyl, halocycloalkyl, alkoxy, benzyloxy, andhaloalkoxy; or a pharmaceutically acceptable salt thereof.
 3. A compoundof claim 1 where R² is hydrogen.
 4. A compound of claim 1 where R³ isAr¹.
 5. A compound of claim 1 where R⁴ is alkyl.
 6. A compound of claim1 where R⁶ is hydrogen, alkyl, haloalkyl, (cycloalkyl)alkyl, (Ar²)alkyl,cycloalkyl, (alkyl)CO, ((cycloalkyl)alkyl)CO, (Ar²)CO, ((Ar²)alkyl)CO,((Ar²)alkyl)OCO, ((Ar²)alkyl)NHCO, or ((Ar²)alkyl)COCO.
 7. A compound ofclaim 1 where N(R⁶)(R⁷) taken together is azetidinyl, pyrrolidinyl,piperidinyl, piperazinyl, morpholinyl, homopiperidinyl, homopiperazinyl,or homomorpholinyl, and is substituted with 0-3 substituents selectedfrom halo, alkyl, haloalkyl, hydroxy, alkoxy, or haloalkoxy.
 8. Acompound of claim 7 where N(R⁶)(R⁷) taken together is pyrrolidinyl orpiperidinyl, and is substituted with 0-3 substituents selected fromhalo, alkyl, haloalkyl, hydroxy, alkoxy, and haloalkoxy.
 9. A compoundof claim 1 where Ar¹ is chromanyl substituted with 0-3 substituentsselected from halo, cyano, alkyl, haloalkyl, cycloalkyl, halocycloalkyl,hydroxy, alkoxy, haloalkoxy, phenoxy, benzyloxy, thioalkyl, andacetamido.
 10. A compound of claim 1 where Ar² is phenyl, pyrazolyl,indolyl, or fluorenonyl, and is substituted with 0-3 substituentsselected from cyano, halo, alkyl, haloalkyl, cycloalkyl, halocycloalkyl,alkoxy, benzyloxy, and haloalkoxy.
 11. A compound of claim 1 where Ar²is phenyl substituted with 0-3 substituents selected from cyano, halo,alkyl, haloalkyl, cycloalkyl, halocycloalkyl, alkoxy, benzyloxy, andhaloalkoxy.
 12. A composition useful for treating HIV infectioncomprising a therapeutic amount of a compound of claim 1 and apharmaceutically acceptable carrier.
 13. The composition of claim 12further comprising a therapeutically effective amount at least one otheragent used for treatment of AIDS or HIV infection selected from thegroup consisting of nucleoside HIV reverse transcriptase inhibitors,non-nucleoside HIV reverse transcriptase inhibitors, HIV proteaseinhibitors, HIV fusion inhibitors, HIV attachment inhibitors, CCR5inhibitors, CXCR4 inhibitors, HIV budding or maturation inhibitors, andHIV integrase inhibitors, and a pharmaceutically acceptable carrier. 14.A method for treating HIV infection comprising administering atherapeutically effective amount of a compound of claim 1, or apharmaceutically acceptable salt thereof, to a patient in need thereof.